title: Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases.
abstract: Signal peptide peptidase (SPP) and the homologous SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 belong to the family of GxGD intramembrane proteases. SPP/SPPLs selectively cleave transmembrane domains in type II orientation and do not require additional co-factors for proteolytic activity. Orthologues of SPP and SPPLs have been identified in other vertebrates, plants, and eukaryotes. In line with their diverse subcellular localisations ranging from the ER (SPP, SPPL2c), the Golgi (SPPL3), the plasma membrane (SPPL2b) to lysosomes/late endosomes (SPPL2a), the different members of the SPP/SPPL family seem to exhibit distinct functions. Here, we review the substrates of these proteases identified to date as well as the current state of knowledge about the physiological implications of these proteolytic events as deduced from in vivo studies. Furthermore, the present knowledge on the structure of intramembrane proteases of the SPP/SPPL family, their cleavage mechanism and their substrate requirements are summarised. This article is part of a Special Issue entitled: Intramembrane Proteases.
authors.affiliation: Adolf Butenandt Institute for Biochemistry, Ludwig-Maximilians University Munich, Schillerstr. 44, 80336 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Voss
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
authors.forename: Regina
authors.initials: R
authors.lastname: Fluhrer
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology*; D005057:Eukaryotic Cells / Q000737:chemistry / Q000201:enzymology*; D005786:Gene Expression Regulation; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry / Q000201:enzymology*; D010802:Phylogeny; D010944:Plants / Q000737:chemistry / Q000201:enzymology; D059748:Proteolysis; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D016282:Aspartic Acid Endopeptidases; C524670:SPPL2a protein, human; C526456:SPPL2b protein, human; C460085:signal peptide peptidase
keywords: GxGD proteases; Intramembrane-cleaving proteases; Regulated intramembrane proteolysis; Signal peptide peptidase; Signal peptide peptidase-like